ABSTRACT The LKB1 (also known as serine/threonine kinase 11, STK11) tumor suppressor is mutationally inactivated in Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by gastrointestinal polyps, mucocutaneous pigmentation, and a markedly increased risk for malignant tumors. Inactivating mutations in LKB1 are also found in cancer patients without PJS, including sporadic lung adenocarcinoma (common), ovarian cancer, breast cancer, pancreatic cancer, and biliary adenocarcinoma (rare). Although LKB1 encodes a protein kinase to which a variety of functions have been ascribed, as yet no unifying hypothesis has convincingly explained how loss of LKB1 function contributes to carcinogenesis. Therefore, the long-term goal of this project is to identify the molecular mechanism underlying the tumor suppressor function of LKB1, a prerequisite for targeting LKB1 function in cancer treatment. In the last decade, considerable evidence has accumulated suggesting that genomic instability plays an important role in tumorigenesis. Supporting a role in tumor suppression, our preliminary findings suggest that LKB1 plays a critical role in maintaining genomic stability. We found that LKB1 interacts with ATM, BRCA1, and other DNA damage response (DDR) proteins in vivo. LKB1-deficient cells exhibit a delayed DDR and reduced DNA repair after exposure to ionizing radiation (IR). LKB1 deficiency enhances intracellular reactive oxygen species (ROS) accumulation, which is a major cause of DNA damage and genetic instability. Ectopic expression of LKB1 reduces intracellular ROS levels. Based on these observations, we hypothesize that LKB1 suppresses tumorigenesis by safeguarding genomic stability through regulating DNA damage/repair response and inhibiting intracellular ROS production. We have designed the following specific aims to test our hypothesis. (1) Determine the role of LKB1 in IR-induced DNA damage/repair response. Hypothesis to be tested: LKB1 is a DDR protein that regulates the enzymes involved in DNA-damage repair and DNA replication. As a corollary, loss of LKB1 may lead to an accumulation of DNA damage, an increase in genomic instability, and augmented tumorigenesis. (2) Determine the role of ROS in the function of LKB1. Hypothesis to be tested: LKB1 protects the genome from ROS-induced oxidative stress by regulating antioxidant gene production. (3) Determine the protein signatures and signaling networks in IR- and H{2}O{2}- treated cells in the presence or absence of LKB1 and identify novel LKB1-interacting proteins under stressed conditions. Hypothesis to be tested: LKB1 interacts with specific proteins to mediate its role in the maintenance of genomic stability. Significance. Accomplishment of these objectives would suggest that LKB1 integrates different signals (DNA damage response, DNA repair, and antioxidant) and interacts with specific proteins in the maintenance of genomic stability. The findings should lead to a better understanding of the role that LKB1 mutation may play in the pathogenesis of PJS and tumorigenesis. These studies will also provide rationale for pharmacologic replacement or mimicry of LKB1 function in cancer prevention and treatment.